The University of Louisville/Jewish Hospital has a remarkably vibrant basic and clinical research program in cardiovascular medicine, particularly in the area of stem cells and patients with heart failure (HF), left ventricular assist devices (LVADs), and ischemic cardiomyopathy. A highly cohesive and collegial team of investigators from the Divisions of Cardiovascular Medicine and Thoracic and Cardiovascular Surgery has worked productively for many years in several multicenter trials, with outstanding performance. This existing clinical infrastructure, coupled with the strong preclinical research work conducted on cell-based therapies for several years, provides a superb platform for participation in the CCTRN as a Regional Clinical Center. The ability of our Center to carry out Phase l/ll studies of stem cells is exemplified by our success i performing the first in-human study of c-kit+ cardiac stem cells in patients with HF (SCIPIO). The same investigators and the infrastructure that made SCIPIO possible will be leveraged for the CCTRN studies. Here we propose SENECA (StEm cell treatmeNt for End stage CArdiac failure), in which we will test the feasibility and safety (Aim 1) and efficacy (Aim 2) of intracoronary delivery of CD34+ cells or very small embryonic-like cells (VSELs) to patients with end-stage ischemic cardiomyopathy (ICM) following implantation of an LVAD. Our hypothesis is that cell therapy will promote repair and regeneration of the injured myocardium, resulting in improved cardiac function, functional capacity, and overall quality of life, and recovery of myocardial function to a degree that permits consideration of LVAD explantation. In Aim 3, we will identify patient characteristics and in vitro parameters of stem cell function that are associated with effectiveness (or lack thereof) of CD34+ cells and VSELs in improving LV function in vivo. SENECA will be the first study of VSELs in humans and the first controlled trial to test the effects of CD34+ cells in end-stage ischemic HF. Therefore, the results will be entirely novel and may provide a new option for patients who currently have a dismal prognosis. Thus, the potential impact of SENECA is considerable. No cell therapy study has ever been reported before in patients with LVADs and ICM, although these are the very patients who need it the most. Therefore, SENECA will address a major therapeutic gap in the management of cardiac patients. This trial has the potential to provide a novel clinical breakthrough in the treatment of end-stage ischemic heart disease.